Breast cancer is the most common cause of cancer death in western women. The majority of breast cancer deaths are due not to the primary tumor but to metastatic disease. Common sites of metastasis include lymph nodes, lung, liver and bone. For example, approximately two thirds of patients with metastatic disease have bone involvement, resulting in severe pain, pathological fractures, hypercalcemia and spinal cord compression. These complications are a significant clinical problem for which there is no effective treatment. The aim of this project is to identify factors that are involved in the metastasis of breast cancer cells to specific sites with the long term objective of developing new diagnostic markers and specific therapies for metastatic disease. Metastasis is a complex process in which cells migrate from the primary tumor to the blood or lymphatic system and hence to distant sites. Many cellular changes and interactions are required during this process. However, our understanding of the process has been hampered by the lack of suitable animal models. We have a unique murine model of breast cancer metastasis comprising genetically matched tumor cell lines all derived from the one spontaneous tumor, that metastasize to different organs such as lymph nodes, lung, liver and bone. Thus, our model provides a powerful system for defining the genetic events that mediate site specific metastasis. The research plan utilizes genetically matched pairs of tumors (from the mouse model) with different metastatic properties to seek differentially expressed genes by cDNA microarray analysis. Once these genes have been identified, expression in human clinical samples will be measured using tumor array technology. Finally, the role in metastasis of relevant genes will be investigated using genetic manipulation of the appropriate tumor cell lines in the mouse metastasis model and in a human breast cancer model. These studies will provide a significant advance in the search for new targets for therapeutic intervention and better diagnostic markers of metastasis.